Cholangiocarcinoma is a cancer of the bile ducts, which drain bile from the liver into the small intestine. Recent evidence has suggested that the liver cancer may arise from a pluripotent hepatic stem cell (Sell and Dunsford Am J. Pathol. 134:1347-1363, 1989). Cholangiocarcinoma entails far lower morbidity worldwide than does liver cancer, with a far higher occurrence in South East Asia than in Europe or North America. Cholangiocarcinoma is not effectively treated by surgical removal because of its high return rate. General chemotherapy and radiotherapy are not useful for the treatment of cholangiocarcinoma (Pederson et al Cancer Res. 4325-4332, 1997) either. In addition, cholangiocarcinoma is difficult to diagnose, and it has been observed that the chronic inflammation, attributed to the infection of bacteria or parasites into the bile ducts, is predisposed to develop into cholangiocarcinoma (Roberts et al., Gastroenterology 112:269-279, 1997).
In spite of the large amount of research results, the pathogenesis of cholangiocarcinoma still remains unknown. Target molecules for the treatment of cholangiocarcinoma are also poorly understood. Only a few cell lines have been established, as a result of some cytogenetic study (Yamaguchi et al., J. Nat'l Cancer Inst 75: 29-35, 1985; Ding et al., Br J Cancer 67: 1007-1010, 1993). However, there has been no report of methods for preparing an antibody specific for cholangiocarcinoma using these cell lines.
Recently, cholangiocarcinoma cell lines Choi-CK and SCK were established from Korean patients suffering from cholangiocarcinoma (Kim et al, Genes, chromosome & Cancer 30:48-56, 2001). If monoclonal antibodies specific to the cell surface are prepared from the mice injected with the cholangiocarcinoma cell line, they can be applied to the treatment of cholangiocarcinoma.
The gene of epidermal growth factor receptor (EGFR), known as a prognostic factor, is a proto-oncogene. EGFR is involved in tumorigenesis and aggressive growth behavior. EGFR is overexpressed in various cancers, including breast cancer, lung cancer, colorectal cancer, kidney cancer, gall bladder carcinoma, head and neck cancer, ovarian cancer, prostate cancer, cancerous cervical tumors, and stomach cancer (Modjtahedi, H. and Dean, C., The receptor for EGF and its ligands: expression, prognostic value and target for therapy in cancer. Int. J. Oncol. 4: 277-296, 1994). In addition, the association of EGFR expression with cancer prognosis differs from one cancer to another (Nicholson, R. I. et al. EGFR and cancer prognosis. Eur. J. Cancer 37, S9-S15, 2001). For example, EGFR can be used as a strong prognosis factor for bladder cancer, cancerous cervical tumors, esophageal cancer, head and neck cancer, and ovarian cancer, but is recognized as a weak prognostic indicator for non-small cell lung carcinoma (NSCLC). However, there is no information known about prognostic factors for cholangiocarcinoma.
When antibodies against EGFR are applied to the treatment of cancers, their inhibitory activity against cancer cell growth was found to vary in efficiency by 15-50% for each cancer type. Also, there is a difference between in vitro and in vivo growth inhibition effects even in the same cancer type (Dassonville, O. et al., EGFR targeting therapies: monoclonal antibodies versus tyrosine kinase inhibitors similarities and differences. Critical Reviews in Oncology/Hematology 62, 53-61, 2007). Currently, antibodies against EGFR are used as therapeutics for colorectal cancer and head and neck cancer, but are not applied to the treatment of all of the above-exemplified cancerous diseases, in which EGFR is overexpressed.
As explained above, expression in cancer cells does not simply guarantee protein to be a prognostic factor for the cancer. Also, whether or not the expression of a protein in cancer cells is associated with cancer prognosis depends on the type of cancer. A strong and poor prognostic factor for cancer can be utilized not only to readily predict the effects of treatment and prognosis of a therapeutic on the cancer, but also to develop a prognostic factor-targeting therapeutic which can be applied selectively and effectively to the cancer of interest. Thus, the discovery of such prognostic factors specific for cancers is very important in the diagnosis and treatment of cancers.
L1 cell adhesion molecule (L1CAM), an integral membrane glycoprotein of 220 kDa, is a member of the immunoglobulin superfamily of cell adhesion molecules (CAMs), which mediate cell-to-cell adhesion on the cell surface. L1CAM, originally identified in neurons (Bateman, et al, EMBO J. 15:6050-6059; 1996), plays a critical role in neural migration, neurite outgrowth and cell migration. The human L1CAM gene was isolated from an embryonic human brain cDNA library using degenerate oligonucleotides derived from L1CAM homologues of mice and rats as probes (Hlavin, M. L. & Lemmon, V. Genomics 11: 416-423, 1991; U.S. Pat. No. 5,872,225, issued on Feb. 16, 1999). L1CAM is expressed primarily in the brain, and its expression is also detected in some normal tissue, and has recently been detected in several types of cancer.
There seems to be an association between L1CAM and cancer. L1CAM has been reported to be expressed in many tumor cell types, including melanoma, neuroblastoma, ovarian carcinoma and colorectal carcinoma (Takeda, et al., J. Neurochem. 66:2338-2349, 1996; Thies et al., Eur. J. Cancer, 38:1708-1716, 2002; Arlt et al., Cancer Res. 66:936-943, 2006; Gavert et al., J. Cell Biol. 168:633-642, 2005). L1CAM has been found not only in the membrane-bound form but also as a cleavage product, which is secreted to the extracellular matrix (Gutwein et al., FASEP J. 17(2):292-4, 2003). Recently, L1CAM has been shown to be a molecule that plays an important role in the growth of tumor cells (Primiano, et al., Cancer Cell. 4(1):41-53 2003) and is arising as a new target for cancer therapy (US2004/0115206 A1, filed on Jun. 17, 2004). Recent studies also showed that L1CAM is expressed at the invasive front of human colon cancer tissue (Gavert, et al., J. Cell Biol. 14; 168(4):633-42. 2005) and anti-L1CAM antibodies function to inhibit the growth and metastasis of ovarian cancer cells (Arlt, et al., Cancer Res. 66:936-943. 2006).
Nowhere is the expression of L1CAM in cholangiocarcinoma cells mentioned in previous reports. Further, there has not yet been any information about whether L1CAM is involved in the growth and metastasis of cholangiocarcinoma. Also, data about whether cholangiocarcinoma patients show higher mortality when L1CAM is expressed at a higher level in the cancer cells, that is, whether L1CAM is a poor prognostic factor for cholangiocarcinoma, have not been published at all. Thus, it was not known prior to the present invention that an antibody against L1CAM has potential as a therapeutic drug by inhibiting the proliferation and metastasis of cholangiocarcinoma, as well.
EP 1,172,654 A1 and U.S. Pat. Publication No. 2004/0259084 disclose a method for the diagnosis and prognosis of an ovarian or endometrial tumors, characterized in that the L1CAM level is determined in a patient sample on the basis that the presence of L1CAM is an indication of the presence of an ovarian or endometrial tumor or a predisposition for such a tumor, and a method of treating ovarian or endometrial tumors in a patient in need of such treatment, comprising administering to the patient a sufficient amount of a L1CAM antibody or a fragment thereof conjugated to a cytotoxic drug. As disclosed in these patents, the L1CAM protein is described only as a marker specific for ovarian or endometrial tumors.
U.S. Pat. Publication No. 2004/0115206 discloses a method and a reagent for inducing cell death in tumor cells using an antibody specifically binding to L1CAM, and pharmaceutical compositions comprising the L1CAM antibody. The method is featured by contacting the tumor cell with an effective amount of an anti-L1CAM antibody for a time and at a concentration sufficient so as to inhibit cell growth or induce cell death in the tumor cell. Mentioning breast cancer, colon cancer and cervical carcinoma cells as examples of L1CAM-expressing tumor cells, this patent publication provides only in-vitro test results, but is not supported by in-vivo data. Nowhere is a relationship between L1CAM and cholangiocarcinoma elucidated therein. Further, this patent publication indicates only that the tumor cell contacts the anti-L1CAM antibody in order to inhibit cell growth and induce cell death, without any suggestion that the anti-L1CAM antibody is able to inhibit the migration, invasion and metastasis of tumor cells.
International Patent Application No. PCT/EP2005/008148 discloses a LICAM protein overexpressed in ovarian and endometrial carcinoma, a pharmaceutical composition for interfering with the expression of L1CAM, and a method for the prevention and treatment of ovarian and endometrial carcinoma using the composition. The pharmaceutical composition, comprising an anti-L1CAM antibody or a derivative thereof, is described as being able to treat ovarian and endometrial carcinoma by inhibiting the migration and growth of the cancer cells. This patent application also mentions only ovarian and endometrial carcinoma in which LICAM in a cell-bound form or a soluble form functions to promote the migration of cancer cells.
In brief, none of the literature prior to the present invention discloses that L1CAM is expressed at high levels in cholangiocarcinoma and can thus be used as a poor prognostic factor specific for cholangiocarcinoma, and that a L1CAM inhibitor, such as an antibody to L1CAM, can accordingly be useful in the diagnosis and treatment of cholangiocarcinoma.